Depression is a psychiatric disorder where disturbance of mood is a prominent feature. Although the etiology of depression is unknown, alterations in serotonergic and noradrenergic function are implicated in the condition. The present Conte Center Grant proposes to examine depression from perspectives of functional imaging, morphometrics, and pharmacological interventions in humans, as well as though mouse genetic, molecular, biochemical, behavioral, and electrophysiological models of depression. The overall objective of the present proposal is to show how the norepinephrine (NE) and serotonin (5-HT) systems are interdependent in the development and amelioration of symptoms of depression, and to reveal novel mechanisms that contribute to the disorder. There are three major Aims. AIM 1: The roles in depression of the NE transporter, 5-HT transporter, and vesicular monoamine transporter 2 will be investigated. Effects of antidepressants on monoamine and metabolite levels in various brain regions will be studied. Molecular fingerprinting of signal transduction pathways will be used to analyze effects of genotype and antidepressant treatment. AIM 2: The role in depression of glycogen synthase kinase-3beta (GSK3b) will be analyzed. Mice will be developed that have GSK3b selectively deleted in the CNS. Animals will be evaluated according to behavioral, neurotransmitter, and signal transduction responses to antidepressants. AIM 3: Mice will be made that bear the same polymorphisms in tryptophan hydroxylase 2 (Tph2) found in human depressed patients. Mutants will be examined according to behavioral, neurotransmitter, and signal transduction responses to antidepressants and electroconvulsive therapy.